Dual function UV-absorbers for ophthalmic lens materials

ABSTRACT

Disclosed are UV absorbers that contain a labile functional group capable of initiating free radical polymerization.

This application claims priority to U.S. Provisional Application, U.S.Ser. No. 60/438,978, filed Jan. 9, 2003.

FIELD OF THE INVENTION

This invention is directed to ophthalmic lens materials. In particular,this invention relates to ultraviolet light absorbers that also act aspolymerization initiators for ophthalmic lens materials.

BACKGROUND OF THE INVENTION

Many UV light absorbers are known as ingredients for polymeric materialsused to make ophthalmic lenses. UV absorbers are preferably covalentlybound to the polymeric network of the lens material instead of simplyphysically entrapped in the material to prevent the absorber frommigrating, phase separating or leaching out of the lens material. Suchstability is particularly important for implantable ophthalmic lenseswhere the leaching of the UV absorber may present both toxicologicalissues and lead to the loss of UV blocking activity in the implant.

Numerous copolymerizable benzatriazole, benzophenone and triazine UVabsorbers are known. Many of these UV absorbers contain conventionalolefinic polymerizable groups, such as methacrylate, acrylate,methacrylamide, acrylamide or styrene groups. Copolymerization withother ingredients in the lens materials, typically with a radicalinitiator, incorporates the UV absorbers into the resulting polymerchain. Incorporation of additional functional groups, on a UV absorbermay influence one or more of the UV absorber's UV absorbing properties,solubility or reactivity. If the UV absorber does not have sufficientsolubility in the remainder of the ophthalmic lens material ingredientsor polymeric lens material, the UV absorber may coalesce into domainsthat could interact with light and result in decreased optical clarityof the lens.

Examples of polymeric ophthalmic lens materials that incorporate UVabsorbers can be found in U.S. Pat. Nos. 5,290,892; 5,331,073 and5,693,095.

SUMMARY OF THE INVENTION

The present invention provides dual function UV absorbers. These UVabsorbers contain a labile functional group capable of initiatingradical polymerization. These UV absorbers are suitable for use inophthalmic lenses, including contact lenses, and are particularly usefulin implantable lenses, such as intraocular lenses (IOLs).

Among other factors, the present invention is based on the finding thatUV absorbers can be modified to incorporate a labile functional groupcapable of initiating polymerization of an olefinic ophthalmic lensmaterial monomers without eliminating the UV absorber's UV absorbingactivity, solubility or reactivity with ophthalmic lens materialingredients.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, all ingredient amounts expressed inpercentage terms are presented as % w/w.

The dual function UV absorbers (“DFUVAS”) of the present inventioncontain a functional group that can initiate free radicalpolymerization. As such, these DFUVAS eliminate the need for twoseparate monomeric ingredients in the preparation of copolymericophthalmic lens materials. Instead of adding a conventional UV absorberto conventional ophthalmic lens-forming materials and separately addinga conventional polymerization initiator, a DFUVAS can be used in placethese two conventional ingredients.

Many conventional thermal free radical initiators and many UV absorbersare known. The DFUVAS may be synthesized by reacting a UV absorber thatcontains a reactive functionality with a radical initiator whilepreserving the radical generating linkage. For example,3-(2H-benzotriazol-2-yl)-4-hydroxyphenethyl alcohol (1) may be coupledto 4,4′-azobis(4-cyanopentanoic acid) (2) using a carbodiimideesterification agent. The product (3) can then initiate radicalpolymerization of a vinyl monomer (e.g., acrylate, methacrylate,acrylamide, methacrylamide, styrene) by application of heat and/orUV/visible light and the UV absorbing functionality will be covalentlyattached to the polymer chain.

This invention provides the synthesis of a single component additivethat provides a dual function: UV absorption properties and ability toinitiate free radical polymerization. The result is a covalently linkedUV absorber that will not leach out of the product or phase separate andlead to decreased optical clarity. The synthesis permits flexibility intailoring both UV absorbing strength and initiator half-life.UV-initiation of polymerization of the lens material is still possiblewith protection of the hydroxy group on the UV absorbing function of theDFUVAS.

The DFUVAS can be synthesized from azo, organic peroxide, phosphineoxide, and α-hydroxyketone radical polymerization initiators thatcontain appropriate functional groups. The necessary functionality fromeach of these initiator classes is the presence of a functional group(carboxylic acid or hydroxyl) through which a UV absorbingbenzotriazole, benzophenone or triazine can be covalently linked.Preferred DFUVAS are those represented by formulas [1]-[7].

Several functionalized azo initiators are commercially available. Forexample, V-501 (4,4′-azobis(4-cyanopentanoic acid)) from Wako Chemicals.This initiator contains a thermally labile azo linkage (—N═N—) and twoterminal carboxylic acid groups. Similarly, VA-086 contains two terminalhydroxyl groups. VA-080 contains three hydroxyl groups on each side ofthe thermally labile azo linkage.

Therefore, an azo functional UV absorber can be synthesized from an azoinitiator with the following structural characteristics:

where:

-   A is —CH₃ or —CH₂CH₃.-   B is —CN, —CO₂H, —COH, —COCH₃, —CO₂CH₃, —SO₃H, —CF₃, or —NO₂ when    (CH₂)_(n), and —CH₃ or —CH₂CH₃ when D is nothing.-   D is nothing or (CH₂)_(n), n=1-10-   E is O or NH, NCH₃, or NCH₂CH₃-   F is nothing, (CH₂)_(x), or (CH₂CH₂O)_(x)CH₂CH₂ where x=1-10.-   G is —R, —OR, —NHR′, —NRR′, —CO₂R, or —COR, where R=a benzotriazole    or benzophenone UV absorber, and R′=—CH₃ or —CH₂CH₃.

Many benzotriazole and benzophenone UV absorbers are known and many arecommercially available from a variety of sources, such as Ciba SpecialtyChemicals. The identity of the benzotriazole or benzophenone UV absorberis not critical, but should be selected based on its characteristic UVcut-off to give the desired UV absorbing property. For IOL applications,preferred benzotriazole UV absorbers are hydroxyphenylbenzotriazoles andpreferred benzophenone UV absorbers are hydroxyphenylbenzophenones thathave been modified to contain a functional group that can be covalentlybonded to a radical polymerization initiator. For example, a preferredhydroxyphenylbenzotriazole UV absorber is2-N-(2-hydroxyphenyl)benzotriazole, where the UV absorbing group islinked through an ethyl ether linkage at the para position on thehydroxyphenyl group, as shown below linked to an azo functionality.

Functionalized α-hydroxyketones suitable for use as UV polymerizationinitiators are commercially available. For example,2-hydroxy-1-[4-(2-hydroxy-ethoxy)phenyl]-2-methylpropan-1-one (Irgacure®2959, Ciba Specialty Chemicals) contains a free primary hydroxyl groupcovalently attached to a UV light labile α-hydroxyketone linkage. Thisprimary hydroxyl can be used as a covalent linking point. For example,in Irgacure® 2959, the primary hydroxyl was used to covalently attachhydrophilic functional groups through an ether linkage to create awater-soluble photoinitiator (Gruber, H. F.; Knaus, S. J. Polym. Sci.Part A: Polym. Chem. 1995, 33, 929).

A generic α-hydroxyketone photoinitiator that contains the appropriatefunctional groups for covalently linking a UV chromophore is representedby formula [2]:

where:

-   J is CH₃ or CH₂CH₃.-   L is nothing, (CH₂)_(y) or (CH₂CH₂O)_(y) where y=1-10.-   G is —R, —OR, —NHR, —NRR′, —CO₂R, or —COR, where R=a benzotriazole    or benzophenone UV absorber, and R′=—CH₃ or —CH₂CH₃.

Functionalized phosphine oxide photoinitiators are also known. Forexample, a vinyl functional phosphine oxide was used in the synthesis ofpolymeric acylphosphine oxide photoinitiators (DeGroot, J. H.;Dillingham, K. A.; Deuring, H.; Haitjema, H. J.; Van Beijma, F. J.;Hodd, K. A.; Norrby, S. Biomacromolecules 2001, 2, 1271).

A generic phosphine oxide photoinitiator that contains the appropriatefunctional groups for covalently linking a UV chromophore is representedby formula [3].

where Q is —H, —CH₃, —CH₂CH₃, —CH(CH₃)CH₃, or —C(CH₃)₃.

-   T is nothing, —(CH₂)_(z), or —(OCH₂CH₂)_(z), where z=1-10-   G is —R, —OR, —NHR, —NRR′, —CO₂R, or —COR, where R=a benzotriazole    or benzophenone UV absorber, and R′=—CH₃ or —CH₂CH₃.

Functionalized organic peroxides are less common, however the presenceof a functional group for example OH, NH₂, or CO₂H would allow covalentattachment of a benzotriazole- or benzophenone-containing UVchromophore. A generic acylperoxide initiator that contains appropriatefunctional groups for covalently linking a UV chromophore is representedby formula [4].

where Y=nothing or O; R=a benzotriazole or benzophenone UV absorber;R′=a benzotriazole or benzophenone UV absorber; —(CH₂)_(n)H (n=1-18);—CH(CH₃) CH₃; —C(CH₃)₃; —C₆H₅; —CH(CH₃)CH₂CH₃; —C(CH₃)₂CH₂C(CH₃)₃;—C(CH₃)₂(CH₂)₄H; —C(CH₂CH₃)₂(CH₂)₄H; —C(CH₃)₂(CH₂)₅H; —C(CH₂CH₃)₂(CH₂)₅H; —C(CH₃)₂(CH₂)₆H; —C(CH₂CH₃)₂(CH₂)₆H; —CH₂CH(CH₂CH₃)(CH₂)₄H; or

By way of illustration, if Y═O and R and R′ in formula [4] are selectedto be the benzotriazole UV absorber 2-N-(2-hydroxyphenyl)benzotriazole,and the UV absorbing group is linked through an ethyl linkage at thepara position on the hydroxyphenyl group to the peroxydicarbonatefunctionality, the following compound is obtained:

Generic peroxyester, dialkylperoxide and peroxyketal initiators thatcontain the appropriate functional groups for covalently linking a UVchromophore are represented by formulas [5], [6], and [7], respectively.

(peroxyester)where R=a benzotriazole or benzophenone UV absorber; R′=a benzotriazoleor benzophenone UV absorber; —(CH₂)_(n)H (n=1-18); —CH(CH₃)CH₃;—C(CH₃)₃; —C₆H₅; —CH(CH₃)CH₂CH₃; —C(CH₃)₂CH₂C(CH₃)₃; —C(CH₃)₂(CH₂)₄H;—C(CH₂CH₃)₂(CH₂)₄H; —C(CH₃)₂(CH₂)₅H; —C(CH₂CH₃)₂(CH₂)₅H;—C(CH₃)₂(CH₂)₆H; —C(CH₂CH₃)₂(CH₂)₆H; —CH₂CH(CH₂CH₃)(CH₂)₄H;—C(CH₃)₂C₆H₅; or

 R—O—O—R (dialkylperoxide)  [6]where R=a benzotriazole or benzophenone UV absorber; R′=H, abenzotriazole or benzophenone UV absorber; —(CH₂)_(n)H (n=1-18);—CH(CH₃)CH₃; —C(CH₃)₃; —CH(CH₃)CH₂CH₃; —C(CH₃)₂CH₂C(CH₃)₃;—C(CH₃)₂(CH₂)₄H; —C(CH₂CH₃)₂(CH₂)₄H; —C(CH₃)₂(CH₂)₅H;—C(CH₂CH₃)₂(CH₂)₅H; —C(CH₃)₂(CH₂)₆H; —C(CH₂CH₃)₂(CH₂)₆H;—CH₂CH(CH₂CH₃)(CH₂)₄H; or —C(CH₃)₂C₆H₅.

where R=a benzotriazole or benzophenone UV absorber;

R′=H; a benzotriazole or benzophenone UV absorber; (CH₂)_(n)H (n=1-18);CH(CH₃)CH₃; C(CH₃)₃; CH(CH₃)CH₂CH₃; C(CH₃)₂C(CH₃)₃; C(CH₃)₂(CH₂)₄H;C(CH₂CH₃)₂(CH₂)₄H; C(CH₃)₂(CH₂)₅H; C(CH₂CH₃)₂(CH₂)₅H; C(CH₃)₂(CH₂)₆H;C(CH₂CH₃)₂(CH₂)₆H; CH₂CH(CH₂CH₃)(CH₂)₄H; or C(CH₃)₂C₆H₅.

In general, the amount of DFUVAS contained in ophthalmic lens materialswill depend upon the desired UV blocking characteristics but willtypically range from 1-5 wt %.

The invention will be further illustrated by the following examples,which are intended to be illustrative, but not limiting.

Example 1 Esterification of 4,4′-azobis(4-cyanopentanoic acid) with3-(2H-benzotriazol-2-yl)-4-hydroxyphenethy alcohol

A 50 mL 3-neck flask was dried in a 120° C. oven overnight and cooled ina desiccator. The flask flushed with N₂ then charged with 1.9151 g (7.50mmol) of 3-(2H-benzotriazol-2-yl)4-hydroxyphenethyl alcohol. The solidwas dissolved in 15 mL anhydrous tetrahydrofuran, then4-dimethylaminopyridine (0.0489 g, 0.400 mmol) and4,4′-azobis(4-cyanopentanoic acid) (1.0084 g, 3.60 mmol), were added andallowed to dissolve. 1,3-Dicyclohexyl carbodiimide (1.5520 g, 7.52 mmol)was added and the reaction mixture was allowed to stir at ambienttemperature under a N₂ blanket for 24 hr. The reaction mixture wasfiltered through a fine porosity sintered glass funnel and the solventwas rotovapped. The crude product was purified by column chromatography(silica gel, CH₂Cl₂), the solvent was rotovapped and the product wasdried under vacuum. Yield 1.3691 g (1.81 mmol, 51%) of a pale yellowpowder.

Example 2 Preparation of Ophthalmic Lens Material initiated with UVabsorbing inititator prepared in Example 1.

A scintillation vial was charged with 3.3572 g (19.052 mmol) of2-phenylethyl acrylate (PEA), 1.5585 g (8.192 mmol) of 2-phenylethylmethacrylate (PEMA), and 0.0611 g (0.308 mmol) of 1,4-butanedioldiacrylate (BDDA). The monomer mixture was purged with N₂ and 0.2290 g(0.304 mmol) of the UV absorbing initiator prepared in Example 1 wasadded and allowed to dissolve. The initiated formulation was filteredthrough a 0.2 micron PTFE filter and dispensed into polypropylene molds.The molds were placed in an oven for 1 hr at 70° C. then 2 hrs at 110°C. The product polymer was extracted in acetone at room temperature for16 hrs. The polymer was allowed to air dry for 1.5 hr, then placed in a60° C. vacuum oven for 3 hrs. The weight loss following extraction wasdetermined gravimetrically and the UV/Vis spectrum was recorded from 190to 820 nm on a 1 mm thick flat. The data is listed in Table 1.

Example 3 Preparation of Ophthalmic Lens Material initiated with UVabsorbing initiator prepared in Example 1.

A scintillation vial was charged with 3.3502 g (19.012 mmol) of2-phenylethyl acrylate (PEA), 1.5516 g (8.156 mmol) of 2-phenylethylmethacrylate (PEMA), and 0.0567 g (0.286 mmol) of 1,4-butanedioldiacrylate (BDDA). The monomer mixture was purged with N₂ and 0.0761 g(0.101 mmol) of the UV absorbing initiator prepared in Example 1 wasadded and allowed to dissolve. The initiated formulation was filteredthrough a 0.2 micron PTFE filter and dispensed into polypropylene molds.The molds were placed in an oven for 1 hr at 70° C. then 2 hrs at 110°C. The product polymer was extracted in acetone at room temperature for16 hrs. The polymer was allowed to air dry for 1.5 hr, then placed in a60° C. vacuum oven for 3 hrs. The weight loss following extraction wasdetermined gravimetrically and the UV/Vis spectrum was recorded from 190to 820 nm on a 1 mm thick flat. The data is listed in Table 1.

Example 4 Preparation of Ophthalmic Lens Material initiated with2,2′-azobisisobutyronitrile (AIBN)

A scintillation vial was charged with 3.3580 g (19.057 mmol) of2-phenylethyl acrylate (PEA), 1.5629 g (8.215 mmol) of 2-phenylethylmethacrylate (PEMA), and 0.0589 g (0.297 mmol) of 1,4-butanedioldiacrylate (BDDA). The monomer mixture was purged with N₂ and 0.0502 g(0.306 mmol) of 2,2′-azobisisobutyronitrile (AIBN) was added and allowedto dissolve. The initiated formulation was filtered through a 0.2 micronPTFE filter and dispensed into polypropylene molds. The molds wereplaced in an oven for 1 hr at 70° C. then 2 hrs at 110° C. The productpolymer was extracted in acetone at room temperature for 16 hrs. Thepolymer was allowed to air dry for 1.5 hr, then placed in a 60° C.vacuum oven for 3 hrs. The weight loss following extraction wasdetermined gravimetrically and the UV/Vis spectrum was recorded from 190to 820 nm on 1 mm thick flat. The data is listed in Table 1.

TABLE 1 Weight % acetone extractables and UV cut-off of ophthalmic lensmaterials. Example % extractables 10% T (nm) 1% T (nm) 2 3.86 ± 0.18 381377 3 4.82 ± 0.25 377 371 4 0.63 ± 0.23 294 279

This invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspecial or essential characteristics. The embodiments described aboveare therefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

1. A dual function UV absorber of the formula:

where: A is —CH₃ or —CH₂CH₃. B is —CN, —CO₂H, —COH, —COCH₃, —CO₂CH₃,—SO₃H, —CF₃, or —NO₂ when D is (CH₂)_(n), and —CH₃ or —CH₂CH₃ when D isnothing. D is nothing or (CH₂)_(n), n=1-10 E is O or NH, NCH₃, orNCH₂CH₃ F is nothing, (CH₂)_(x) or (CH₂CH₂O)_(x)CH₂CH₂ where x=1-10. Gis —R, —OR, —NHR, —NRR′, —CO₂R, or —COR, whereR=hydroxyphenylbenzotriazole, and R′=—CH₃ or —CH₂CH₃.
 2. An ophthalmiclens material comprising a dual function UV absorber of claim
 1. 3. Theophthalmic lens material of claim 2 wherein the dual function UVabsorber is present in the ophthalmic lens material in an amount of 1-5%(w/w).
 4. The dual function UV absorber of claim 1 whereinR=2-N-(2-hydroxyphenyl)benzotriazole.